The CB1 receptor is one of the main G-coupled seven membrane receptor (GCPR) of the body. It is the principal GCPR of the brain and it is also expressed by most body tissues including, but not limited to, the adipose tissue, liver, pancreas, muscles, kidney, bladder and the bones.
The CB1 is activated by endogenous ligands named endocannabinoids including, but not limited to, Anandamide and 2-arachidonyl glycerol (2-AG).
Through activation by endogenous ligands, the CB1 has been involved in the regulation of a large number of physiological functions and pathological states. A non exhaustive list of the functions in which the activation of the CB1 receptor has been involved include: energy metabolism; inflammation and immunity; fibrosis, bone homeostasis; lipid storage and accumulation in various organs, behaviors; self-administration of drugs of abuse, memory, stress-related adaptation, behaviors mediated by positive reinforcers; gastrointestinal motility and motility of other visceral contractile organs; cell proliferation and differentiation; pain regulation; reproduction and fertility. (Marsicano et al., J Endocrinol Invest., 2006; 29(3 Suppl):27-46 Review; Pagotto U et al., Int J. Obes. 2006, Suppl 1:S39-43 Review; Pagotto U et al., Endocr Rev., 2006 (1):73-100. Review; Bifulco M, et al. Mol. Pharmacol. 2007, 71(6):1445-56 Review)
Because of this wide spread physiological role, over-activation of the CB1 receptor has been involved in a large number of pathologies, diseases and pathophysiological processes. A non exhaustive list of examples of diseases and diseases-related process in which the activation of the CB1 receptor has been involved include: bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; metabolic disorders; obesity; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders; autoimmune hepatitis and encephalitis; pain; reproductive disorders and skin inflammatory and fibrotic diseases. (Di Marzo et al., Nat. Rev., Drug Discov., 2004, 3: 771-784).
The CB1 receptor is the major target of Δ9tetrahydrocannabinol (THC), the active principle contained in the drugs of abuse obtained from Cannabis sativa. It is through CB1 activation that THC exercises its addictive effects and its behavioral and physiological disrupting effects. In addition the CB1 receptor is also involved in mediating the effects of all the other known drugs of abuse, including, but not limited to, nicotine, opioids, psychostimulants and alcohol. The CB1 receptor is also involved in mediating the appetitive properties of non-drug reinforcing stimuli that are able to induce addiction, including, but not limited to, food, sexual partners or gambling. The general effects of CB1 on drugs of abuse and other reinforcing stimuli that are able to induce addiction is explained by the excitatory control that activation of the CB1 receptor exercise on the activity of the dopaminergic transmission. Thus, activation of the dopaminergic transmission is involved in mediating the appetitive properties and addictive liability of drug of abuse and non-drug positive reinforcers. For this reason a blockade of CB1 activity has been proposed as a method for treating addiction, drug abuse, drug dependence and relapse (Scherma M et al., CNS Neurol Disord Drug Targets. 2008; 7(5):468-81. Review; Wiskerke J et al., Addict Biol. 2008; 13(2):225-38. Review; Moreira F A, et al., Addict Biol. 2008; 13(2):196-212. Review; López-Moreno J A et al, Addict. Biol. 2008; 13(2):160-87. Review; Janero D R et al., Curr Psychiatry Rep., 2007; 9(5):365-73. Review; Laviolette S R et al., Cell Mol Life Sci., 2006; 63(14):1597-613. Review; Maldonado R, et al. Trends Neurosci., 2006; 29(4):225-32. Review; Colombo G et al., Pharmacol Biochem Behav., 2005; 81(2):369-80. Review; Gardner E L. Pharmacol Biochem Behav., 2005; 81(2):263-84. Review).
Inhibition of the CB1 receptor has been shown to reduce weight and enhance improvements in cardiometabolic risk parameters. Thus, CB1 receptor antagonists have been shown to prophylactically prevent overweight, to assist in regulating food intake, to assist as a diet aid, to treat obesity and ameliorate metabolic disorders often associated with obesity such as diabetes and dislipedimia. (Bermudez-Silva F J et al., 2010; Lee H K et al. 2009; Xie S et al., 2007).
Central CB1 receptor signaling is functionally linked to monoaminergic neurotransmission. This makes CB1 antagonists candidates for the treatment of psychosis, affective and cognitive disorders brought about by disturbances in any of the central monoaminergic systems. Furthermore, CB1 agonists lead to memory impairment. CB1 antagonists are therefore good candidate agents for memory enhancement (see Reibaud M et al., Eur. J. Pharmacol, 1999; 379 (1):R1-2, and Terranova J P et al, Psychopharmacology., 1996; 126(2): 165-72). CB1 activation can also lead to impairment in movement and movement disorders like Parkinson's disease have been associated with elevated brain endocannabinoids. CB1 antagonism would therefore be a good candidate treatment for Parkinson's disease (see Di Marzo V et al, FASEB J., 2000; 14(10): 1432-8). Therefore, CB1 antagonists are candidates to treatment of various psychiatric and neurological diseases.
CB1 receptor is also involved in spasticity as disclosed by Pryce G et al., (Br J Pharmacol, 2007, 150 (4): 519-525.) and by Baker D. et al. (FASEB J., 2001, 15: 300-302).
Chien F Y, et al. have shown that WIN 55212-2, a cannabinoid agonist at the CB(1) receptor, reduces intraocular pressure in both normal and glaucomatous monkey eyes. CB1 receptors are expressed in some peripheral tissues such as nerve endings in the gastrointestinal tract depress gastrointestinal motility, mainly by inhibiting ongoing contractile transmitter release. Antagonists of CB1 receptor could thus find use in pathological states consisting of decreased intestinal motility such as Paralytic ileus caused by peritonitis, surgery, or other noxious situations (Mascolo N et al, FASEB J., 2002 December; 16(14): 1973-5).
Also about gastrointestinal diseases, CB1 receptors are also shown to be involved in liver diseases and in particular in liver steatosis, steatohepatitis (NASH) and cirrosis. The CB1 activation play a role in these diseases by a double mechanism: 1. Promoting the accumulation of fat in the liver; 2. Promoting the release of inflammatory factor such as TNFα. CB1 inhibitor are beneficial in these pathologies because they both reduce fat accumulation and the release of THFα. 3. In this case For examples see: 1. Mallat A and Lotersztajn S. Diabetes and Metabolis 34 (2008) 680-684; 2. Tam J et al., HEPATOLOGY 2011; 53:346-355; 3. Sören V. Siegmund S V and Schwabe R F Am J Physiol Gastrointest Liver Physiol 294: G357-G362, 2008; 4. DeLeve D L et al., The American Journal of Pathology, 173, No. 4, 2008; 5. Roche M et al., Immunology, 2008 125, 263-271; 6. Murumalla R et al., Journal of Inflammation 2011, 8:33; 7. Croci T, et al., British Journal of Pharmacology (2003) 140, 115-122.
CB1 receptors are also expressed in noradrenergic terminals innervating the bone. CB1 activation is able to inhibit Noradrenaline release in the bone which in turn increases osteoclaste activity decreasing bone mass, including, but not limited to menopause associated osteoporosis. For this reason CB1 antagonists have also been proposed as a treatment for osteoporosis. (Idris A I Curr Neuropharmacol. 2010 8(3):243-53.
CB1 receptors also play a role in vascular endothelial cells where they mediate the hypotensive effects of platelet and macrophage-derived endocannabinoids. CB1 antagonists would be useful agents in inhibiting endotoxin-induced or cirrhotic hypotension (see Batkai S et al, Nat. Med., 2001 July; 7(7): 827-32) both of which are characterized by elevated levels of endocannabinoids. CB1 also stimulate angiogenesis, as a consequence blockade of the CB1 receptor has been proposed for the treatment of diseases in which an increase in angiogenesis plays a pathophyisiological role as for example in tumor development.
CB1 receptors have also been involved in pathologies of the cardiovascular system including cardiomiopathies such as cyrrotic cardiomiopathy and antideoplastic drugs induced cardiomiopathies, contractile disfunction, infarction and atherosclerosis. The CB1 receptors play a role in these diseases with multiple mechanisms that involve control of blood pressure, inflammation, lipid accumulation, vascularisation and heart contractility. For example see: 1. Bákal S et al., Am J Physiol Heart Circ Physiol. 2007, 293: H1689-H1695; 2. Seyed Ali Gaskari S A et al., British Journal of Pharmacology (2005) 146, 315-323; 3. Bátkai S and Pacher P. Pharmacol Res. 2009, 60: 99-106. 4. Nissen S E et al., JAMA. 2008; 299(13): 1547-1560. 5. Mukhopadhyay P et al., J Am Coll Cardiol. 2007, 50: 528-536.
CB1 receptors have also been shown to be involved in inflammatory diseases and in particular but not limited to in skin diseases including skin inflammation, skin inflammation and cancer induced by UV, skin fibrosis and wound healing. In this context an inhibition or suppression of the CB1 receptor has been shown beneficial for all these pathological states. For example see: 1. Marquart S et al., ARTHRITIS & RHEUMATISM, 2010, 62:3467-3476; 2. Zheng D et al., Cancer Res. 2008 May 15; 68(10): 3992-3998.
Furthermore, endocannabinoid signalling is found in some human malignancies compared with the corresponding healthy tissues, as well as in human cancer cells with a high degree of invasiveness (Sarnataro D et al., 2006; Gazzerro P et al., 2010; Santoro A, et al. 2009).
The endocannabinoid signalling is also implied in fertilization, preimplantation embryo and spermatogenesis and it is therefore a relevant target to improve infertility and reproductive health in humans.
For these reasons the inhibition of the CB1 receptor has been suggested as a therapy of all these pathological states and associated diseases.
Methods aimed at blocking the activity of the CB1 through inhibition of the orthosteric binding site, the site at which the endogenous ligands bind to activate the receptor, have been developed and submitted for clinical trials. One of these compounds, rimonabant, has even been put on the market with the brand name Acomplia. Acomplia has been tested and revealed a beneficial effect for the treatment of metabolic disorders, diabetes and dyslipidemia, obesity and also in one study for nicotine addiction.
Unfortunately, available orthosteric antagonists such as rimonabant also act as inverse agonists of the CB1 receptor, i.e. they not only inhibit the activation of the CB1, but also the basal activity of the receptor in the absence of the endogenous ligand. Because of this inverse agonist action and the total inhibition of the receptor activity, available methods based on the administration of orthosteric CB1 antagonists also have a series of serious adverse effects. Because of these adverse effects commercialization of Acomplia has been suspended and the development of other methods inhibiting the orthosteric site of the CB1 stopped.
Many of the pathologies for which ortostheric antagonists of the CB1 receptor have demonstrated good therapeutic efficacy are still in need of new efficient therapies. There is consequently need to develop methods that can allow to inhibit the CB1 receptor without interfering with orthosteric binding and have less side effects than orthosteric antagonists.
Therefore, there is still a need to develop ligands that allow an inhibition of the CB1 receptors without modifying the orthosteric binding or inducing adverse effects.